A5077990667- CAR-T cell therapy research
- Sarcoma Diagnosis and Treatment
- RNA modifications and cancer
- RNA Interference and Gene Delivery
- Neuroblastoma Research and Treatments
- Eosinophilic Disorders and Syndromes
- MicroRNA in disease regulation
- Fibroblast Growth Factor Research
- ATP Synthase and ATPases Research
- Microtubule and mitosis dynamics
- Virus-based gene therapy research
- Vascular Tumors and Angiosarcomas
- Protist diversity and phylogeny
- Endoplasmic Reticulum Stress and Disease
- Cancer therapeutics and mechanisms
- Immune Cell Function and Interaction
- Signaling Pathways in Disease
- Monoclonal and Polyclonal Antibodies Research
- Circular RNAs in diseases
- Immunotherapy and Immune Responses
- Cancer-related molecular mechanisms research
- Machine Learning in Bioinformatics
- Cancer, Hypoxia, and Metabolism
- Extracellular vesicles in disease
- Cell death mechanisms and regulation
Center for Cancer Research
2012-2024
National Cancer Institute
2010-2024
National Institutes of Health
2008-2024
Leidos (United States)
2014-2018
Leidos Biomedical Research Inc. (United States)
2018
Mayo Clinic in Florida
2014
University of Hawaiʻi at Mānoa
2014
University of Hawaii System
2014
Frederick National Laboratory for Cancer Research
2014
Science Applications International Corporation (United States)
2009-2010
Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 highly expressed RMS tissue, suggesting role tumorigenesis, although its functional importance has not defined. Here, we report identification mutations human tumors lead to activation present evidence it functions as an oncogene RMS. Higher...
Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated (TAAs), limited persistence, and exhaustion. Here, we aimed identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed neuroblastoma (NB), a lethal extracranial tumor childhood. First, examined CAR expansion the presence targets by digital droplet PCR....
With investigators looking to expand engineered T cell therapies such as CAR-T new tumor targets and patient populations, a variety of manufacturing platforms have been developed scale capacity using closed and/or automated systems. Such are particularly useful for solid targets, which typically require higher doses. Although phenotype function key attributes that often correlate with therapeutic efficacy, how influence the final product is currently unknown. We compared 4 commonly used...
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) cell surface tyrosine kinase receptor that involved normal myogenesis and muscle regeneration, but not commonly expressed differentiated tissues. Amplification mutational activation of FGFR4 has been reported RMS promotes tumor progression. Therefore, tractable...
MicroRNA 34a (miR-34a) is a potential tumor suppressor gene and has been identified as miRNA component of the p53 network. To better understand biological pathways involved in miR-34a action, parallel global protein mRNA expression profiling on treated neuroblastoma cells (IMR32) was performed using isotope-coded affinity tags (ICAT) Affymetrix U133plus2 microarray, respectively. Global showed that causes much smaller changes compared to at level. A total 1495 proteins represented by two or...
Genome-wide association studies (GWAS) of 10 different cancers have identified pleiotropic cancer predisposition loci across a region chromosome 5p15.33 that includes the TERT and CLPTM1L genes. Of these, susceptibility alleles for pancreatic mapped to gene, thus prompting an investigation function in pancreas. Immunofluorescence analysis indicated localized endoplasmic reticulum where it is likely embedded membrane, accord with multiple predicted transmembrane domains. Overexpression...
Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. Treatment outcomes, particularly for relapsed/refractory or metastatic disease, have not improved decades. The current lack of novel therapies and low tumor mutational burden suggest that chimeric antigen receptor (CAR) T-cell therapy could be a promising approach to treating RMS. Previous work identified FGF 4 (FGFR4, CD334) as being specifically upregulated RMS, making it candidate target CAR T cells. We...
CD19 chimeric antigen receptor T-cell therapy (CD19-CAR) has changed the treatment landscape and outcomes for patients with pre-B-cell acute lymphoblastic leukemia (B-ALL). Unfortunately, primary nonresponse (PNR), sustained CD19+ disease, concurrent expansion of CD19-CAR occur in 20% is associated adverse outcomes. Although some failures may be attributable to loss, mechanisms CD19-independent, leukemia-intrinsic resistance remain poorly understood. We hypothesize that PNR leukemias are...
Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor 4 (FGFR4) highly expressed in RMS lowly healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as adoptive T cell treatment for RMS. 3A11 CAR cells induced robust cytokine production...
Abstract Background: Rhabdomyosarcoma (RMS) is the most common pediatric sarcoma, representing 3-4% of childhood and adolescent cancers. While multimodal therapies improved outcomes for localized disease, 5-year survival relapsed or metastatic RMS cases remains poor. Antibody-drug conjugates (ADCs) use specificity monoclonal antibodies to selectively deliver potent anticancer chemotherapy agents tumor cells while sparing healthy tissues. FGFR4, a cell-surface receptor tyrosine kinase highly...
microRNAs have been shown to be involved in different human cancers. We therefore performed expression profiles on a panel of pediatric tumors identify cancer-specific microRNAs. also investigated if are coregulated with their host gene.We parallel and mRNA profiling 57 tumor xenografts cell lines representing 10 solid using microarrays. For those that map mRNA, we calculated correlations between them.We found the majority cancer types clustered together based global microRNA by unsupervised...
Neuroblastoma is one of the most genomically heterogeneous childhood malignances studied to date, and molecular events that occur during course disease are not fully understood. Genomic studies in neuroblastoma have showed only a few recurrent mutations low somatic mutation burden. However, none these has examined arising disease, nor they systemically expression mutant genes. Here we performed genomic analyses on tumors taken 3.5 years from patient (bone marrow biopsy at diagnosis, adrenal...
Abstract Chimeric antigen receptor (CAR) T-cells targeting Fibroblast Growth Factor Receptor 4 (FGFR4), a highly expressed surface tyrosine in rhabdomyosarcoma (RMS), are already the clinical phase of development, but tumour heterogeneity and suboptimal activation might hamper their potency. Here we report an optimization strategy co-stimulatory properties FGFR4 CAR. We replace CD8 hinge transmembrane domain 4-1BB with those CD28. The resulting CARs display enhanced anti-tumor activity...
AbstractSynthetic triterpenoids, such as 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives, are an extremely potent class of new anti-cancer therapeutic agents, characterized by high anti-tumor potency low toxicity to normal tissues. This report is the first investigate effects C-28 derivatives CDDO on 22 pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, osteosarcoma, Ewing's sarcoma. We determined IC50s in range 5 – 170 nM for inhibition...
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs two cell lines, SK-N-AS and SH-SY5Y. We found 30 compounds that were active lines at < or =10 microM concentration. More interestingly, 17 are =1 concentration, they act through wide spectrum diverse mechanisms such as mitotic inhibition,...
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring need novel treatments. FGFR4, a receptor tyrosine kinase that overexpressed in RMS mutationally activated 10% cases, promising target treatment. Here, we show futibatinib, an irreversible pan-FGFR inhibitor, inhibits growth cell lines vitro by inhibiting phosphorylation FGFR4 its...
Abstract Background Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim this study was to identify novel combination chemotherapy improve rate in neuroblastoma. Methods We took a synthetic lethal approach using siRNA library targeting 418 apoptosis-related genes and identified pathways whose inhibition synergized topotecan. Microarray analyses cells treated topotecan were performed if same or altered by drug. An...
Abstract Rhabdomyosarcoma (RMS), an aggressive soft tissue sarcoma originating from skeletal muscle in children and adolescent young adults. It is divided two main histological subtypes including embryonal RMS driven by RAS pathway mutations alveolar a chimeric fusion gene involving PAX3 or PAX7 with FOXO1. FGFR4 cell surface tyrosine kinase receptor that critical molecule biology. In it direct target strongly induced PAX3-FOXO1 as well PAX3, PAX7. By immunohistochemistry we found high...
Whole-cell vaccines allow the induction of anti-tumor immune responses without need to define tumor antigens. We wished directly compare, for first time, capacity B7-1, B7-2 and 4-1BB ligand (4-1BBL) costimulatory molecules convert murine human acute myeloid leukemia (AML) cells into whole vaccines. 32Dc-kit is a cell line, which develops an AML-like disease over protracted period, emulating AML development. were modified express elevated levels or 4-1BBL, each led rejection, although only...
Abstract Background Rhabdomyosarcoma (RMS) is the most common pediatric sarcoma, representing 3-4% of childhood and adolescent cancers. Although multimodal therapies have significantly improved overall survival patients with localized disease, 5-year for relapsed metastatic disease has remained dismal. Therefore, new are desperately needed this deadly disease. Antibody-drug conjugates (ADCs) combine specificity monoclonal antibodies cytotoxic potency chemotherapy drugs to selectively deliver...